Reticulon/Nogo (RTN/Nogo) proteins are critical factors in neurological and neurodegenerative disorders. In our previous funding cycle, we investigated potential roles of neuronal RTN3 in the negative modulation of BACE1 proteolytic activity. We demonstrated that increased expression of RTN3 in mice reduced amyloid deposition in cortical brain regions. However, this increased expression of RTN3 also facilitated the formation of RTN3 immunoreactive dystrophic neurites (RIDNs) in the hippocampus, and the occurrence of RIDNs impaired hippocampal synaptic function. These results suggest that RTN3 can play two opposing roles in the formation of neuritic plaques, in which amyloid deposits are often surrounded by various dystrophic neurites (including RIDNs) and reactive glial cells. In this proposal, we aim to investigate how these two seemingly opposing roles can be dissociated. We hypothesize that somatodendritic RTN3 modulates BACE1 activity, and that aggregated axonal RTN3 facilitates the formation of dystrophic neurites. We will perform a set of experiments utilizing four animal models (Tg-RTN3 mice, RTN3 transgenic mice under Tet-Off inducible promoter, RTN1 and RTN3 KO mice) generated in our lab to test this hypothesis, specifically addressing the following specific aims: 1) To investigate the effect of RTN protein levels on the formation RIDNs; 2) To explore the pathophysiological consequence of RIDNs; 3) To determine the in vivo role of RTN proteins in the formation of neuritic plaques. Moreover, we have found that RIDNs naturally occur in the elderly mouse brain. To further understand their occurrence in elderly human brains, we will address an additional specific aim, to identify and characterize RIDNs in human brains. Postmortem brains from at least two different sources will be used to address this specific aim. We will determine whether RIDNs occur in elderly human brains and whether this occurrence is significantly more frequent in AD brains. The results from the above studies will provide further evidence that RIDNs represent an early stage of dystrophic neurites in elderly and AD brains and that reducing RIDNs is an important novel drug target with the aim of improving cognitive function in the elderly population and AD patients.